Jasmonates are a family of plant stress hormones, derived from linolenic acid by the octadecanoid pathway, and are found in minute quantities in many edible plants. Stress hormones such as the jasmonate family, have evolved in plants, and are released in such times of stress such as extreme UV radiation, osmotic shock, heat shock and pathogen attack to initiate various cascades which end in appropriate responses. Examples of members of the jasmonate family are jasmonic acid, which is crucial to intracellular signaling in response to injury, and methyl jasmonate, which causes induction of a proteinase inhibitor that accumulates at low concentrations in response to wounding or pathogenic attacks. Jasmonates have been patented for a variety of uses in plant growth and crop improvement, but have not been previously known for use in medicine. Use of jasmonates for the treatment of mammalian cancer has been disclosed in U.S. Pat. No. 6,469,061, reference to which is incorporated hereby in its entirety. In U.S. Pat. No. 6,469,061, it was shown that jasmonates were directly cytotoxic for various types of human cancer cells derived from breast, prostate, skin and blood cancers. While jasmonates elicited death in human leukemic Molt-4 cells, they did not damage normal lymphocytes.
Subsequent data collected similarly showed that jasmonates do not damage healthy erythrocytes (see WO 02/080890). In U.S. Pat. No. 6,469,061, one jasmonate compound in particular, methyl jasmonate, was shown to be effective in preventing development of lymphomas in mice. See also Fingrut, O. and E. Flescher. 2002. “Plant stress hormones suppress the proliferation and induce apoptosis in human cancer cells”, Leukemia 16: 608-616 (2002).
The pharmacological activity of jasmonate compounds makes them attractive candidates as therapeutic agents for the treatment of cancer. Because only a few jasmonate derivatives have been reported (see, for example, Ishii et al., Leukemia, 1-7 (2004)), a need in the art exists to develop jasmonate derivative compounds that are potent chemotherapeutic drugs, with a high degree of specificity towards malignant cells.
The present invention addresses this need, and provides other advantages as well.